VOLUME
33
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20
2015
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Personalized Radiation Oncology for Breast Cancer: The New Frontier Jennifer R. Bellon, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA See accompanying article on page 2035
Radiation therapy (RT) to the breast after breast-conserving surgery (BCS) is considered a standard of care for most women with early-stage invasive breast cancer.1 Adjuvant RT has repeatedly been shown to decrease the risk of an in-breast recurrence. Although no single study has shown a survival benefit to the addition of RT, a meta-analysis of randomized studies1 including 10,801 patients showed a 10-year reduction in any first recurrence from 35% to 19.3% with radiation (P ⬍ .001), which translated to a 3.8% absolute improvement in breast cancer–specific survival at 15 years (25.2% to 21.4%; P ⬍ .001). However, the survival benefit was not uniform across all risk groups. When stratified by absolute difference in 10-year risk of recurrence, patients who experienced an improvement greater than 20% with RT had a corresponding 7.8% difference in 15-year breast cancer mortality. However, for patients with an absolute improvement less than 10%, the breast cancer mortality benefit was only 0.1% (absolute mortality reduction trend P ⫽ .03). Moreover, RT is inconvenient, has some toxicity,2 and adds costs to the health care system.3 Identifying a group of patients with sufficiently low risk of recurrence, such that RT has no meaningful impact on survival and can therefore be reasonably omitted, has therefore been the goal of multiple randomized and single-arm studies. Patients in these early trials were selected largely by anatomic features of their pathology rather than by characterization of the tumor’s biology. The Harvard hospitals initiated a prospective trial of lumpectomy alone in putatively favorable T1N0 cancers with wide surgical margins in 19864 in an attempt to identify a favorable subgroup of patients in whom RT could be avoided. Estrogen receptor (ER) status was unknown in 50% of those patients. The study was closed prematurely when stopping rules were met as a result of a 23% crude local recurrence (LR) rate at a median of 86 months of followup. A randomized trial of 264 women from Finland also attempted to identify a group of women with a low rate of LR without RT.5 Despite widely negative surgical margins, the rate of LR was significantly lower with adjuvant RT than with BCS alone (P ⫽ .0013). The National Survival Adjuvant Breast and Bowel Project B-21 trial (NSABP B-21)6 asked a similar question for women with tumors smaller than 1.0 cm. One thousand nine women were randomly assigned to receive tamoxifen, RT, or both. LR was significantly higher in women not receiving radiation, with an 8-year cumulative incidence of LR of 16.5% with tamoxifen alone, 9.3% with RT alone, and 2.8% with tamoxifen and RT. Even in this series of women with small but otherwise unselected tumors, there was still a benefit with RT. More recently Cancer and 1998
© 2015 by American Society of Clinical Oncology
Leukemia Group B trial 9343 (CALGB 9343)7 also found a reduction in LR with RT in women older than age 70 years with T1N0 (clinically or pathologically) ER-positive early-stage disease, although the benefit to RT was quite modest in this elderly population. During the past 15 years, there has been increased awareness that early-stage breast cancer represents a heterogeneous group of diseases defined by unique molecular subtypes.8,9 Given the wide availability of immunohistochemistry techniques, ER, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as well as markers of proliferation and grade have typically been used to approximate these molecular subtypes. However, attention has largely focused on subtype and the risk of distant disease. More recently, the impact of subtype on LR has also been appreciated. Arvold et al10 examined the risk of LR in 1,434 patients who underwent BCS and RT; 91% also received systemic therapy. The authors found a 5-year cumulative risk of LR of 2.1% (95% CI, 1.4% to 3.0%) for the group as a whole. This compares favorably with rates seen in the largely older studies, likely because of the increased use of effective systemic therapy.11,12 However, when specifically looking at a subset of 905 patients with luminal A disease—approximated by ER- or PR-positive, HER2negative status and low or intermediate grade—the risk of LR was only 0.8% (95% CI, 0.4% to 1.8%). Several other series in the breast conservation and mastectomy settings13-15 as well as a meta-analysis16 including more than 12,000 patients have corroborated these findings. Other efforts to group patients on the basis of the biologic character of their tumors have focused on gene expression profiling. Although initial research focused on predicting the risk of distant recurrence,17 improved tumor characterization may also help inform the risk of LR as well. Mamounas et al18 looked at the risk of LR in patients with node-negative disease from NSABP B-14 and B-20 by using the OncotypeDX (Genomic Health, Redwood City, CA) recurrence score (RS). RS was significantly associated with LR across all systemic therapy treatment groups and, after multivariable analysis, independently predicted for LR. In patients with node-positive disease treated on NSABP B-28, RS was also highly predictive of LR (P ⬍ .001).19 After multivariable analysis, RS was more closely associated with LR (hazard ratio [HR], 2.86) than with other traditional factors, including the number of involved nodes (ⱖ 4 v 1-3; HR, 2.08) or tumor size (HR, 1.26). It is conceivable that a gene panel designed specifically to look at the risk of LR may yield an even more accurate risk assessment. Nonetheless, the possibility of a biologic indicator Journal of Clinical Oncology, Vol 33, No 18 (June 20), 2015: pp 1998-2000
Information downloaded from jco.ascopubs.org and provided by at CAMBRIDGE UNIV MEDICAL LIBRARY on August 10, Copyright © 2015 American of Clinical Oncology. All rights reserved. 2015Society from 131.111.164.128
Editorial
more closely associated with LR than is nodal involvement challenges traditional assumptions regarding adjuvant radiation and suggests the beginning of a new paradigm for determining adjuvant local therapy recommendations. Given the overall lower rates of LR seen in modern studies after BCS and RT coupled with the possibility of being able to more precisely stratify patients on the basis of risk of recurrence with RT, the question of omitting RT in the treatment of patients with early-stage disease once again comes to the forefront. The reanalysis of the prospective Toronto/British Columbia trial by Liu et al that accompanies this editorial20 is a positive step forward in this regard. The original trial randomly assigned patients older than age 50 years with nodenegative tumors smaller than 5.0 cm to tamoxifen alone or to tamoxifen with whole-breast RT. In their initial publication,20a 5-year LR was 0.6% with tamoxifen and RT compared with 7.7% with just tamoxifen (P ⬍ .001). Even in a planned selected subset of patients with T1 and ER-positive tumors, LR at 8 years was still substantially lower with RT than with tamoxifen alone (3.6% v 15.2%; P ⬍ .001). In the present study, the authors constructed tissue microarrays from 501 (65%) of the original tumor blocks. Tumors were then classified into six molecular subtypes according to immunohistochemistry determination of ER, PR, HER2, CK5/6, epidermal growth factor receptor, and Ki-67. Patients were grouped according to luminal A, luminal B, and because of small numbers, high-risk disease categories (luminal-HER2, HER2 enriched, basal-like and triple-negative nonbasal). The randomized nature of the study provides a unique look into not just whether subtype is prognostic of outcome but also whether subtype predicts benefit from RT. As demonstrated in multiple retrospective studies,10,13-15 subtype was prognostic for LR. At 10 years, patients with luminal A disease had a 5.2% risk of LR compared with 21.3% in those with high-risk subtypes. In an attempt to identify a favorable group of patients, Liu et al20 defined a combined subset by using both clinical and pathologic factors. In this exploratory subset of 151 patients with luminal A tumors and low-risk features (defined as older than age 60 years, T1, and grade 1/2), LR was only 1.3% at 10 years with tamoxifen alone. Although patients with luminal A tumors experienced a smaller benefit from RT (HR, 0.40) than did those with high-risk tumors, the interaction between RT and subtype was not significant (P ⫽ .26). As Liu et al suggest, the small benefit from RT among patients with luminal A tumors likely results from the low event rate in both arms. A possible radiosensitivity of luminal A tumors was seen in a retrospective analysis of the combined Danish 82b and C postmastectomy radiation trials,21 in which patients with receptor-positive, HER2negative tumors experienced a significantly greater benefit from RT than patients with triple-negative disease. At present, the possibility of varying radiosensitivity according to subgroup remains speculative. Clearly, additional research is needed in other cohorts to determine not only whether subtype is predictive of RT response but also how this should dictate treatment. This study,20 coupled with the earlier subtype-based analyses, paves the way for other prospective initiatives using the tumor’s biologic identity to select patients with such a low risk of LR that RT can be avoided without adversely affecting survival. LUMINA, from the Ontario Clinical Oncology Group, is a prospective single-arm study of BCS and endocrine therapy without RT in women with T1N0 luminal A cancers ages 55 years and older (Clinicaltrials.gov identifier NCT01791829). Jagsi et al at the University of Michigan are launching www.jco.org
a multi-institutional prospective single-arm trial in women ages 50 to 69 years with ER-positive, PR-positive, and HER2-negative early-stage tumors with OncotypeDX RS of ⱕ 18 who will receive hormonal therapy. The Dana-Farber Cancer Institute is also initiating a multiinstitutional single-arm study of BCS and hormonal therapy without RT in women age 50 to 75 with ER positive and HER2 negative, grade 1 or 2, T1N0 tumors with luminal A characterization by the PAM5022 gene expression signature. Long-term follow-up in these trials will be necessary to fully characterize the extent of recurrence, given the late pattern of events seen with luminal A tumors.23 Overtreatment remains a significant issue in the adjuvant management of treatment for women with early-stage breast cancer. Ideally, increasingly sophisticated characterization of each individual tumor will permit tailoring of treatment more closely to each patient; in doing so, it may allow for the omission of RT in those who are unlikely to benefit. The new frontier of personalized radiation oncology for breast cancer is in sight. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the author are available with this article at www.jco.org. REFERENCES 1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S, McGale P, et al: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:17071716, 2011 2. Darby SC, Ewertz M, Hall P: Ischemic heart disease after breast cancer radiotherapy. N Engl J Med 368:2527, 2013 3. Suh WW, Pierce LJ, Vicini FA, et al: A cost comparison analysis of partial versus whole-breast irradiation after breast-conserving surgery for early-stage breast cancer. Int J Radiat Oncol Biol Phys 62:790-796, 2005 4. Lim M, Bellon JR, Gelman R, et al: A prospective study of conservative surgery without radiation therapy in select patients with stage I breast cancer. Int J Radiat Oncol Biol Phys 65:1149-1154, 2006 5. Holli K, Hietanen P, Saaristo R, et al: Radiotherapy after segmental resection of breast cancer with favorable prognostic features: 12-year follow-up results of a randomized trial. J Clin Oncol 27:927-932, 2009 6. Fisher B, Bryant J, Dignam JJ, et al: Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 20:41414149, 2002 7. Hughes KS, Schnaper LA, Bellon JR, et al: Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: Long-term follow-up of CALGB 9343. J Clin Oncol 31:2382-2387, 2013 8. Sørlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001 9. Perou CM, Sørlie T, Eisen MB, et al: Molecular portraits of human breast tumours. Nature 406:747-752, 2000 10. Arvold ND, Taghian AG, Niemierko A, et al: Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy. J Clin Oncol 29:3885-3891, 2011 11. Sartor CI, Peterson BL, Woolf S, et al: Effect of addition of adjuvant paclitaxel on radiotherapy delivery and locoregional control of node-positive breast cancer: Cancer and Leukemia Group B 9344. J Clin Oncol 23:30-40, 2005 12. Anderson SJ, Wapnir I, Dignam JJ, et al: Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by breast-conserving therapy in five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative breast cancer. J Clin Oncol 27:2466-2473, 2009 13. Millar EK, Graham PH, O’Toole SA, et al: Prediction of local recurrence, distant metastases, and death after breast-conserving therapy in early-stage invasive breast cancer using a five-biomarker panel. J Clin Oncol 27:47014708, 2009
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at CAMBRIDGE UNIV MEDICAL LIBRARY on August 10, Copyright © 2015 American of Clinical Oncology. All rights reserved. 2015Society from 131.111.164.128
1999
Editorial
14. Voduc KD, Cheang MC, Tyldesley S, et al: Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol 28:1684-1691, 2010 15. Dominici LS, Mittendorf EA, Wang X, et al: Implications of constructed biologic subtype and its relationship to locoregional recurrence following mastectomy. Breast Cancer Res 14:R82, 2012 16. Lowery AJ, Kell MR, Glynn RW, et al: Locoregional recurrence after breast cancer surgery: A systematic review by receptor phenotype. Breast Cancer Res Treat 133:831-841, 2012 17. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004 18. Mamounas EP, Tang G, Fisher B, et al: Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor–positive breast cancer: Results from NSABP B-14 and NSABP B-20. J Clin Oncol 28:1677-1683, 2010 19. Mamounas EP Tang G Paik S, et al: The 21-gene recurrence score (RS) predicts risk of loco-regional recurrence (LRR) in node (⫹), ER(⫹) breast cancer (BC) after chemotherapy and tamoxifen: Results from NSABP B-28. Ann Surg Onc 20:s6-164, 2013 (abstr 2)
20. Liu F-F, Shi W, Done SJ, et al: Identification of a low-risk luminal A breast cancer cohort that may not benefit from breast radiotherapy. J Clin Oncol 33:2035-2040, 2015 20a. Fyles AW, McCready DR, Manchul LA, et al: Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med 351:963-970, 2004 21. Kyndi M, Sørensen FB, Knudsen H, et al: Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: The Danish Breast Cancer Cooperative Group. J Clin Oncol 26:1419-1426, 2008 22. Prat A, Parker JS, Fan C, et al: PAM50 assay and the three-gene model for identifying the major and clinically relevant molecular subtypes of breast cancer. Breast Cancer Res Treat 135:301-306, 2012 23. Foulkes WD, Smith IE, Reis-Filho JS, et al: Triple-negative breast cancer. N Engl J Med 363:1938-1948, 2010
DOI: 10.1200/JCO.2015.61.2069; published online ahead of print at www.jco.org on May 11, 2015
■ ■ ■
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2000
© 2015 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
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Editorial
AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Personalized Radiation Oncology for Breast Cancer: The New Frontier The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Jennifer R. Bellon No relationship to disclose
www.jco.org
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at CAMBRIDGE UNIV MEDICAL LIBRARY on August 10, Copyright © 2015 American of Clinical Oncology. All rights reserved. 2015Society from 131.111.164.128
Editorial
Acknowledgment I thank Jay R. Harris, MD, for his invaluable guidance in preparing this article.
© 2015 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at CAMBRIDGE UNIV MEDICAL LIBRARY on August 10, Copyright © 2015 American of Clinical Oncology. All rights reserved. 2015Society from 131.111.164.128
33
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JUNE
20
2015
JOURNAL OF CLINICAL ONCOLOGY
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Personalized Radiation Oncology for Breast Cancer: The New Frontier Jennifer R. Bellon, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA See accompanying article on page 2035
Radiation therapy (RT) to the breast after breast-conserving surgery (BCS) is considered a standard of care for most women with early-stage invasive breast cancer.1 Adjuvant RT has repeatedly been shown to decrease the risk of an in-breast recurrence. Although no single study has shown a survival benefit to the addition of RT, a meta-analysis of randomized studies1 including 10,801 patients showed a 10-year reduction in any first recurrence from 35% to 19.3% with radiation (P ⬍ .001), which translated to a 3.8% absolute improvement in breast cancer–specific survival at 15 years (25.2% to 21.4%; P ⬍ .001). However, the survival benefit was not uniform across all risk groups. When stratified by absolute difference in 10-year risk of recurrence, patients who experienced an improvement greater than 20% with RT had a corresponding 7.8% difference in 15-year breast cancer mortality. However, for patients with an absolute improvement less than 10%, the breast cancer mortality benefit was only 0.1% (absolute mortality reduction trend P ⫽ .03). Moreover, RT is inconvenient, has some toxicity,2 and adds costs to the health care system.3 Identifying a group of patients with sufficiently low risk of recurrence, such that RT has no meaningful impact on survival and can therefore be reasonably omitted, has therefore been the goal of multiple randomized and single-arm studies. Patients in these early trials were selected largely by anatomic features of their pathology rather than by characterization of the tumor’s biology. The Harvard hospitals initiated a prospective trial of lumpectomy alone in putatively favorable T1N0 cancers with wide surgical margins in 19864 in an attempt to identify a favorable subgroup of patients in whom RT could be avoided. Estrogen receptor (ER) status was unknown in 50% of those patients. The study was closed prematurely when stopping rules were met as a result of a 23% crude local recurrence (LR) rate at a median of 86 months of followup. A randomized trial of 264 women from Finland also attempted to identify a group of women with a low rate of LR without RT.5 Despite widely negative surgical margins, the rate of LR was significantly lower with adjuvant RT than with BCS alone (P ⫽ .0013). The National Survival Adjuvant Breast and Bowel Project B-21 trial (NSABP B-21)6 asked a similar question for women with tumors smaller than 1.0 cm. One thousand nine women were randomly assigned to receive tamoxifen, RT, or both. LR was significantly higher in women not receiving radiation, with an 8-year cumulative incidence of LR of 16.5% with tamoxifen alone, 9.3% with RT alone, and 2.8% with tamoxifen and RT. Even in this series of women with small but otherwise unselected tumors, there was still a benefit with RT. More recently Cancer and 1998
© 2015 by American Society of Clinical Oncology
Leukemia Group B trial 9343 (CALGB 9343)7 also found a reduction in LR with RT in women older than age 70 years with T1N0 (clinically or pathologically) ER-positive early-stage disease, although the benefit to RT was quite modest in this elderly population. During the past 15 years, there has been increased awareness that early-stage breast cancer represents a heterogeneous group of diseases defined by unique molecular subtypes.8,9 Given the wide availability of immunohistochemistry techniques, ER, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as well as markers of proliferation and grade have typically been used to approximate these molecular subtypes. However, attention has largely focused on subtype and the risk of distant disease. More recently, the impact of subtype on LR has also been appreciated. Arvold et al10 examined the risk of LR in 1,434 patients who underwent BCS and RT; 91% also received systemic therapy. The authors found a 5-year cumulative risk of LR of 2.1% (95% CI, 1.4% to 3.0%) for the group as a whole. This compares favorably with rates seen in the largely older studies, likely because of the increased use of effective systemic therapy.11,12 However, when specifically looking at a subset of 905 patients with luminal A disease—approximated by ER- or PR-positive, HER2negative status and low or intermediate grade—the risk of LR was only 0.8% (95% CI, 0.4% to 1.8%). Several other series in the breast conservation and mastectomy settings13-15 as well as a meta-analysis16 including more than 12,000 patients have corroborated these findings. Other efforts to group patients on the basis of the biologic character of their tumors have focused on gene expression profiling. Although initial research focused on predicting the risk of distant recurrence,17 improved tumor characterization may also help inform the risk of LR as well. Mamounas et al18 looked at the risk of LR in patients with node-negative disease from NSABP B-14 and B-20 by using the OncotypeDX (Genomic Health, Redwood City, CA) recurrence score (RS). RS was significantly associated with LR across all systemic therapy treatment groups and, after multivariable analysis, independently predicted for LR. In patients with node-positive disease treated on NSABP B-28, RS was also highly predictive of LR (P ⬍ .001).19 After multivariable analysis, RS was more closely associated with LR (hazard ratio [HR], 2.86) than with other traditional factors, including the number of involved nodes (ⱖ 4 v 1-3; HR, 2.08) or tumor size (HR, 1.26). It is conceivable that a gene panel designed specifically to look at the risk of LR may yield an even more accurate risk assessment. Nonetheless, the possibility of a biologic indicator Journal of Clinical Oncology, Vol 33, No 18 (June 20), 2015: pp 1998-2000
Information downloaded from jco.ascopubs.org and provided by at CAMBRIDGE UNIV MEDICAL LIBRARY on August 10, Copyright © 2015 American of Clinical Oncology. All rights reserved. 2015Society from 131.111.164.128
Editorial
more closely associated with LR than is nodal involvement challenges traditional assumptions regarding adjuvant radiation and suggests the beginning of a new paradigm for determining adjuvant local therapy recommendations. Given the overall lower rates of LR seen in modern studies after BCS and RT coupled with the possibility of being able to more precisely stratify patients on the basis of risk of recurrence with RT, the question of omitting RT in the treatment of patients with early-stage disease once again comes to the forefront. The reanalysis of the prospective Toronto/British Columbia trial by Liu et al that accompanies this editorial20 is a positive step forward in this regard. The original trial randomly assigned patients older than age 50 years with nodenegative tumors smaller than 5.0 cm to tamoxifen alone or to tamoxifen with whole-breast RT. In their initial publication,20a 5-year LR was 0.6% with tamoxifen and RT compared with 7.7% with just tamoxifen (P ⬍ .001). Even in a planned selected subset of patients with T1 and ER-positive tumors, LR at 8 years was still substantially lower with RT than with tamoxifen alone (3.6% v 15.2%; P ⬍ .001). In the present study, the authors constructed tissue microarrays from 501 (65%) of the original tumor blocks. Tumors were then classified into six molecular subtypes according to immunohistochemistry determination of ER, PR, HER2, CK5/6, epidermal growth factor receptor, and Ki-67. Patients were grouped according to luminal A, luminal B, and because of small numbers, high-risk disease categories (luminal-HER2, HER2 enriched, basal-like and triple-negative nonbasal). The randomized nature of the study provides a unique look into not just whether subtype is prognostic of outcome but also whether subtype predicts benefit from RT. As demonstrated in multiple retrospective studies,10,13-15 subtype was prognostic for LR. At 10 years, patients with luminal A disease had a 5.2% risk of LR compared with 21.3% in those with high-risk subtypes. In an attempt to identify a favorable group of patients, Liu et al20 defined a combined subset by using both clinical and pathologic factors. In this exploratory subset of 151 patients with luminal A tumors and low-risk features (defined as older than age 60 years, T1, and grade 1/2), LR was only 1.3% at 10 years with tamoxifen alone. Although patients with luminal A tumors experienced a smaller benefit from RT (HR, 0.40) than did those with high-risk tumors, the interaction between RT and subtype was not significant (P ⫽ .26). As Liu et al suggest, the small benefit from RT among patients with luminal A tumors likely results from the low event rate in both arms. A possible radiosensitivity of luminal A tumors was seen in a retrospective analysis of the combined Danish 82b and C postmastectomy radiation trials,21 in which patients with receptor-positive, HER2negative tumors experienced a significantly greater benefit from RT than patients with triple-negative disease. At present, the possibility of varying radiosensitivity according to subgroup remains speculative. Clearly, additional research is needed in other cohorts to determine not only whether subtype is predictive of RT response but also how this should dictate treatment. This study,20 coupled with the earlier subtype-based analyses, paves the way for other prospective initiatives using the tumor’s biologic identity to select patients with such a low risk of LR that RT can be avoided without adversely affecting survival. LUMINA, from the Ontario Clinical Oncology Group, is a prospective single-arm study of BCS and endocrine therapy without RT in women with T1N0 luminal A cancers ages 55 years and older (Clinicaltrials.gov identifier NCT01791829). Jagsi et al at the University of Michigan are launching www.jco.org
a multi-institutional prospective single-arm trial in women ages 50 to 69 years with ER-positive, PR-positive, and HER2-negative early-stage tumors with OncotypeDX RS of ⱕ 18 who will receive hormonal therapy. The Dana-Farber Cancer Institute is also initiating a multiinstitutional single-arm study of BCS and hormonal therapy without RT in women age 50 to 75 with ER positive and HER2 negative, grade 1 or 2, T1N0 tumors with luminal A characterization by the PAM5022 gene expression signature. Long-term follow-up in these trials will be necessary to fully characterize the extent of recurrence, given the late pattern of events seen with luminal A tumors.23 Overtreatment remains a significant issue in the adjuvant management of treatment for women with early-stage breast cancer. Ideally, increasingly sophisticated characterization of each individual tumor will permit tailoring of treatment more closely to each patient; in doing so, it may allow for the omission of RT in those who are unlikely to benefit. The new frontier of personalized radiation oncology for breast cancer is in sight. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the author are available with this article at www.jco.org. REFERENCES 1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S, McGale P, et al: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:17071716, 2011 2. Darby SC, Ewertz M, Hall P: Ischemic heart disease after breast cancer radiotherapy. N Engl J Med 368:2527, 2013 3. Suh WW, Pierce LJ, Vicini FA, et al: A cost comparison analysis of partial versus whole-breast irradiation after breast-conserving surgery for early-stage breast cancer. Int J Radiat Oncol Biol Phys 62:790-796, 2005 4. Lim M, Bellon JR, Gelman R, et al: A prospective study of conservative surgery without radiation therapy in select patients with stage I breast cancer. Int J Radiat Oncol Biol Phys 65:1149-1154, 2006 5. Holli K, Hietanen P, Saaristo R, et al: Radiotherapy after segmental resection of breast cancer with favorable prognostic features: 12-year follow-up results of a randomized trial. J Clin Oncol 27:927-932, 2009 6. Fisher B, Bryant J, Dignam JJ, et al: Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 20:41414149, 2002 7. Hughes KS, Schnaper LA, Bellon JR, et al: Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: Long-term follow-up of CALGB 9343. J Clin Oncol 31:2382-2387, 2013 8. Sørlie T, Perou CM, Tibshirani R, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98:10869-10874, 2001 9. Perou CM, Sørlie T, Eisen MB, et al: Molecular portraits of human breast tumours. Nature 406:747-752, 2000 10. Arvold ND, Taghian AG, Niemierko A, et al: Age, breast cancer subtype approximation, and local recurrence after breast-conserving therapy. J Clin Oncol 29:3885-3891, 2011 11. Sartor CI, Peterson BL, Woolf S, et al: Effect of addition of adjuvant paclitaxel on radiotherapy delivery and locoregional control of node-positive breast cancer: Cancer and Leukemia Group B 9344. J Clin Oncol 23:30-40, 2005 12. Anderson SJ, Wapnir I, Dignam JJ, et al: Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in patients treated by breast-conserving therapy in five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative breast cancer. J Clin Oncol 27:2466-2473, 2009 13. Millar EK, Graham PH, O’Toole SA, et al: Prediction of local recurrence, distant metastases, and death after breast-conserving therapy in early-stage invasive breast cancer using a five-biomarker panel. J Clin Oncol 27:47014708, 2009
© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at CAMBRIDGE UNIV MEDICAL LIBRARY on August 10, Copyright © 2015 American of Clinical Oncology. All rights reserved. 2015Society from 131.111.164.128
1999
Editorial
14. Voduc KD, Cheang MC, Tyldesley S, et al: Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol 28:1684-1691, 2010 15. Dominici LS, Mittendorf EA, Wang X, et al: Implications of constructed biologic subtype and its relationship to locoregional recurrence following mastectomy. Breast Cancer Res 14:R82, 2012 16. Lowery AJ, Kell MR, Glynn RW, et al: Locoregional recurrence after breast cancer surgery: A systematic review by receptor phenotype. Breast Cancer Res Treat 133:831-841, 2012 17. Paik S, Shak S, Tang G, et al: A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817-2826, 2004 18. Mamounas EP, Tang G, Fisher B, et al: Association between the 21-gene recurrence score assay and risk of locoregional recurrence in node-negative, estrogen receptor–positive breast cancer: Results from NSABP B-14 and NSABP B-20. J Clin Oncol 28:1677-1683, 2010 19. Mamounas EP Tang G Paik S, et al: The 21-gene recurrence score (RS) predicts risk of loco-regional recurrence (LRR) in node (⫹), ER(⫹) breast cancer (BC) after chemotherapy and tamoxifen: Results from NSABP B-28. Ann Surg Onc 20:s6-164, 2013 (abstr 2)
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DOI: 10.1200/JCO.2015.61.2069; published online ahead of print at www.jco.org on May 11, 2015
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AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Personalized Radiation Oncology for Breast Cancer: The New Frontier The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Jennifer R. Bellon No relationship to disclose
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© 2015 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at CAMBRIDGE UNIV MEDICAL LIBRARY on August 10, Copyright © 2015 American of Clinical Oncology. All rights reserved. 2015Society from 131.111.164.128
Editorial
Acknowledgment I thank Jay R. Harris, MD, for his invaluable guidance in preparing this article.
© 2015 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at CAMBRIDGE UNIV MEDICAL LIBRARY on August 10, Copyright © 2015 American of Clinical Oncology. All rights reserved. 2015Society from 131.111.164.128
